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RATIONALE Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP). OBJECTIVES Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP. METHODS Next generation sequences from two CHP cohorts were analyzed to identify variants in TERT, TERC, DKC1, RTEL1, PARN, and TINF2. To qualify, variants were required to have a minor allele frequency <0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using qPCR. MEASUREMENTS AND MAIN RESULTS Qualifying variants were identified in 16/144 patients (11.1%, 95% CI 6.5-17.4) in the discovery cohort and 17/209 patients (8.1%, 95% CI 4.8-12.7) in the replication cohort. Age and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 base pairs [bp], 95% CI -933 to -190, p=0.003; replication: -612 bp, 95% CI -870 to -354, p=5.30x10-6) cohorts. Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-sex-ancestry-adjusted hazard ratio [HR] 3.73, 95% CI 1.92-7.28, p=0.0001; replication: HR 2.72, 95% CI 1.26-5.88, p=0.011). CONCLUSIONS A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.